The effects of upper body blood flow restriction training on muscles located proximal to the applied occlusive pressure: A systematic review with meta-analysis

Background Blood flow restriction combined with low load resistance training (LL-BFRT) is associated with increases in upper limb muscle strength and size. The effect of LL-BFRT on upper limb muscles located proximal to the BFR cuff application is unclear. Objective The aim of this systematic review was to evaluate the effect of LL-BFRT compared to low load, or high load resistance training (LL-RT, HL-RT) on musculature located proximal to cuff placement. Methods Six electronic databases were searched for randomized controlled trials (RCTs). Two reviewers independently evaluated the risk of bias using the PEDro scale. We performed a meta-analysis using a random effects model, or calculated mean differences (fixed-effect) where appropriate. We judged the certainty of evidence using the GRADE approach. Results The systematic literature searched yielded 346 articles, of which 9 studies were eligible. The evidence for all outcomes was of very low to low certainty. Across all comparisons, a significant increase in bench press and shoulder flexion strength was found in favor of LL-BFRT compared to LL-RT, and in shoulder lean mass and pectoralis major thickness in favor of the LL-BFRT compared to LL-RT and HL-RT, respectively. No significant differences were found between LL-BFRT and HL-RT in muscle strength. Conclusion With low certainty LL-BFRT appears to be equally effective to HL-RT for improving muscle strength in upper body muscles located proximal to the BFR stimulus in healthy adults. Furthermore, LL-BFRT may induce muscle size increase, but these adaptations are not superior to LL-RT or HL-RT.

Introduction Muscular hypertrophy and muscle strength improvements have been traditionally linked to a heavy-load resistance training (HL-RT) program [1]. According to the American College of Exercise Medicine resistance training load of~60-70% of the one repetition maximum (1RM) is required to achieve improvements in muscle strength and 70-85% of 1 RM for gains in muscle hypertrophy [1]. However, such high loads are frequently not attainable in the clinical setting due the characteristics associated with musculoskeletal conditions such as the healing process, pain, muscle weakness, and functional or loading limitations [2].
Recently, significant attention has been drawn to low load resistance training (LL-RT) combined with blood flow restriction (BFR), which involves a parallel partial restriction of the arterial flow and complete occlusion of the venous return of the exercised limb [3,4]. BFR is applied by using inflatable cuffs with an individually adjusted amount of compressed air placed at the most proximal part of the exercised limb [3]. Usually, the BFR cuff is applied at the deltoid tuberosity for an upper limb application and at the gluteal fold for a lower limb application [4].
Mounting evidence suggests that the use of BFR combined with LL-RT (20-40% of 1RM) may offer an applicable alternative to exercise with heavy-loads in improvement of muscle size and muscle strength [5][6][7][8]. Interestingly, studies have shown that these adaptations may occur even after a period of only three weeks of application with a training frequency of 2-3 times a week [9,10]. In addition, low-load BFR training (LL-BFRT) has been found to be equally effective to traditional strength training in patients with knee osteoarthritis [11,12], after a knee surgery including an ACL reconstruction [13], and in patients with anterior knee pain [14].
The effectiveness of this training method in improving muscle strength and hypertrophy has been consistently reported in the literature, but the exact mechanisms of action are still under investigation [4,15]. Several hypotheses have been proposed with the higher levels of metabolic stress due to ischemic/hypoxic conditions being the most plausible mediator through several physiological pathways [16]. These mechanisms may include increases in hormonal concentrations, increases within the components of the intracellular signaling pathways for muscle protein synthesis-such as the mTOR pathway, increases within biomarkers denoting satellite cell activity, and patterns in fiber type recruitment [17].
While a significant number of studies focusing on the application of BFRT in the lower extremity have been published, research in the upper extremity is sparse [18][19][20][21]. A plausible explanation can be attributed to the anatomical location of the large muscle groups of the upper extremity (e.g., pectoralis major, deltoid, latissimus dorsi) that humpers the proximal application of the cuff and the restriction of the blood flow in contrast to lower extremity where the large muscle groups are located mainly distal (e.g., quadriceps) to the applied occlusive pressure [15].
Recently emerging evidence in healthy individuals revealed promising outcomes indicating that the use of LL-BFRT may result in increased muscle strength and hypertrophy in muscles located proximal to the BFR cuff application [15][16][17][18][19][20][21][22]. However, the published research until today remains sparse. Hence, the main objective of this systematic review of randomized controlled trials (RCTs) was to evaluate in healthy individuals the effectiveness of LL-BFRT in inducing muscle adaptations, such as changes in muscle size and strength, in muscle groups surrounding the shoulder girdle and located proximally to the BFR cuff and the applied occlusive pressure.

Protocol and guidelines
This systematic review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [23] and followed the recommendations of the Cochrane Handbook for Systematic Reviews [24].

Eligibility criteria
The primary eligibility criteria were formulated based on the Population, Intervention, Comparison, Outcome, Study design (PICOS) framework [25] and were predefined as follows: 1. Population: healthy individuals (no age restriction).
2. Intervention: performance of LL-BFRT of the upper limb with the BFR cuff or elastic band applied before exercise, the limb remained restricted until exercise completion, and employed a training protocol consisted of at least five sessions to allow sufficient time for measurable muscle adaptations [9].
3. Comparison: a comparator group performing low, medium, or high load exercise of the upper limb. 4. Outcomes: pre-and post-training measures of muscle size and/or strength of muscles located proximally to the shoulder. 5. Study design: randomized controlled trials or quasi-experimental study designs written in the English language.

Information sources and search strategy
The search was conducted independently by two reviewers (KP and CK) from database inception to May 2022 using the following databases and clinical trial registries: MEDLINE (PubMed), CINAHL (EBSCO), SPORTDiscus (EBSCO), SCOPUS, EU clinical trials, and Clin-icalTrials.gov. The search strategy consisted of MeSH terms and keywords (synonyms and abbreviations) related to the BFR and the shoulder or the upper limb, combined with MeSH terms for RCTs. The full search strategy is presented in S1 Table of S1 File. The reference lists, citation tracking results, and systematic reviews were manually searched to identify studies that were not found through database searching.

Study selection and data extraction
Final search results were imported into EndNote and duplicates were removed. Two reviewers (KP and VK) independently evaluated titles and abstracts, and the full text of the potentially eligible studies was obtained and evaluated, while disagreements were resolved by a third reviewer (CS). One author (KP) abstracted relevant details about study design, sample size, demographic characteristics, attrition rate, BFR and exercise protocol (type, frequency, occlusion characteristics, training load, and duration), pre-and post-intervention means and standard deviation for any strength or muscle size measures, and main within-and between-group results (strength and muscle size). A second investigator (VK) reviewed all data for accuracy. In case of missing data authors were contacted via email (twice). Data presented only in graphs were converted and obtained by using WebPlotDigitizer software (Version 4.5, https:// automeris.io/WebPlotDigitizer/).

Quality assessment and risk of bias
Two investigators (KP and VK) independently evaluated study quality using the Physiotherapy Evidence Database (PEDro) scale which is considered as a valid and reliable tool for assessing the internal and external validity of RCTs [26,27]. Discrepancies were resolved through consensus.
The PEDro scale consists of ten items assessing the randomization and allocation process, the blinding, the baseline comparability, and the study reporting [27]. Studies scoring �7/10 were rated as "high quality", studies with a score 4 to 6/10 as "moderate quality", and those with score �3 as "low quality" studies [12,19]. A PEDro quality score <7 indicated a study as having a "high" risk of bias [28].

Data analysis, synthesis, and intervention effect
Using the available outcome measures for muscle size and strength, we calculated standardized mean differences (SMDs) and the associated 95% confidence intervals (95%CI) where data from more than one study was available, after appraising the variability of clinical settings and methods used for strength and muscle size assessment. We calculated and presented mean differences (MDs) in the case of a single study data availability [29]. When two or more studies were available pair-wise meta-analyses were conducted and forest plots were presented if aggregate pooled estimates met the sample and intervention homogeneity criteria. We pooled pair-wise meta-analyses assessing the same muscle group, using similar methods of strength and muscle volume assessment, which evaluated muscle loading of comparable magnitude where recruited participants displayed comparable demographic characteristics, and after leave-one-out sensitivity analyses.
When only one study was available for an outcome an effect size (MD, fixed effect model) was calculated and presented. Results per outcome and muscle group were presented as summary tables. For the effect estimates the Review Manager V.5.3 statistical software of the Nordic Cochrane Collaboration was used and assuming methodological and setting heterogeneity between studies, a random effects meta synthesis was employed where applicable. Strength values were transformed in kilograms for analyses, where applicable.
If considerable between-group statistical heterogeneity was detected (i.e., I 2 > 75%), we did not perform a meta-analysis [29], but evaluated the heterogeneity with sensitivity analyses by excluding studies with unexpectedly large treatment effect sizes and 'leave-one-out' exclusion, and studies presenting significant heterogeneity at baseline for participant characteristics. Given the small number of included studies, assessment of reporting bias with a funnel plot was not possible.

Certainty of evidence
Two investigators (KP and GP) independently evaluated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology [31,32] and created and exported tables using the gradepro software (https:// gdt.gradepro.org/). Quality of the evidence was rated as "high", "moderate", "low" or "very low" depending on the presence of: risk of bias, inconsistency, indirectness, imprecision, publication bias (where applicable) ( Table 1). Any disagreements were resolved by discussion and involvement of a third investigator (CK).
In the case of a single trial outcome, we a-priori graded the evidence as "low certainty", and if the study had a "high risk" of bias the evidence was downgraded to "very low certainty" [33].

Study characteristics and participants
Study characteristics such as, sample size, age, gender, interventions, intervention parameters, loading progressions, and main findings are presented in Table 2. All included studies recruited healthy participants (n = 218) of which the majority were male (73%) with a mean pooled age of 26.5 years (mean range 19.2 to 60.5 years). Five studies [37][38][39][40][41] recruited only male and one study [42] only female participants. The median number of participants randomized per trial was 24 (IQR 11-32) and the sample size ranged from 9 to 46.

Intervention characteristics
The training duration ranged from 2 to 8 weeks (median = 3, IQR 2-3), with 2 to 8 exercise sessions per week (median = 2.5, IQR 2-3, range 2 to 6). Three studies [34][35][36] used only shoulder muscle exercises, two studies [37,42] a combination of shoulder, chest, and back muscle exercises, while four [38][39][40][41] only the bench press exercise ( Table 2). With regards to BFRT, all studies implemented 4 sets for each exercise with the same number of repetitions (75 total), except one study [43] that participants were instructed to perform the fourth set to volitional exhaustion and another study [39] that participants performed 100 repetitions in total. LL-RT and HL-RT groups used the same exercises with the BFRT group in every study, with a more variable protocol in terms of sets and repetitions; nevertheless, in 5 out of 9 included studies the comparator group shadowed the exercise volume of the BFRT group. Between-set rest ranged from 30 to 45 seconds and between-exercise rest from 30 secs to 2 minutes (Table 2). In all studies the training load was based on 1RM or maximum voluntary isometric contraction (MVIC). The BFRT training intensities were always low (10-30% of 1RM), while two studies gradually increased the training load from 10% to 30% and from 20% to 32% of the 1RM, respectively [38,42]. The control group training intensities ranged from low intensity [34-36, 39, 40] to high intensity (65-90% of 1RM) [37,38,41,42] ( Table 2). Four studies used automatically adjusted individualized cuff pressure ranging from 50% to 60% of the total vascular limb occlusion pressure (LOP) [34][35][36][37], two studies [38,42] based the LOP to the RPE during exercising, while 4 of the included studies [38][39][40][41] applied an elastic band for the limb occlusion. Three studies [40][41][42] applied an incremental increase (weekly) of the occlusion pressure during the intervention based on predefined (not individualized) mmHg pressure (Table 2) [42]. Finally, one study [39] did not specify the used LOP.

Adverse events
Only one study [34] assessed adverse events and none were reported.

Effects of interventions in muscle strength
Muscle strength in LL-BFRT compared to LL-RT without BFR. Five studies [34-36, 39, 40] evaluated the effect of LL-BFRT compared to LL-RT, of which only one was of low risk of bias [34] in a range of muscle movements using isokinetic or hand-held dynamometry (S2 Table in S1 File).
Three studies [34][35][36] evaluated shoulder external rotation strength and reported inconsistent between-group results affected by testing position and measurement method. Pooled results from two studies [35,36] showed very low certainty evidence of no significant differences between comparators in shoulder isometric external rotation at 90˚of abduction in prone strength but significant and unexplained heterogeneity (SMD = 0.96, I 2 = 92%) (S1a Fig  in S1 File). Inconsistent results of low and very low-quality evidence were presented for shoulder external rotation strength in seated and in prone position; however, both studies [34,36] that evaluated strength in seated position did not report significant between-group differences ( Table 4).
Two studies [34,36] evaluated shoulder internal rotation using different settings and reported low and very low certainty evidence of inconsistent results in individual-study calculated effect sizes at the 8-week follow-up (Table 4).
Shoulder abduction [34,35] and scaption [34,36] were evaluated in studies potentially using different measurement methodology (lack of information in one [34] and the evidence should be interpreted with caution. Pooled results for each outcome presented substantial  heterogeneity (I 2 >75%), thus we did not perform a formal meta-analysis (S1b and S1c Fig in S1 File). By calculating MDs for each study, inconsistent results showed low certainty evidence in favor of LL-BRT in abduction and scaption, strength of the shoulder from one study [34] and very low certainty evidence of no difference between the comparators in abduction and scaption shoulder strength from another study [36] (Table 4).

Muscle strength in LL-BFRT compared to HL-RT.
Four studies [37,38,41,42] with high risk of bias evaluated the effects of LL-BFR training compared to HL-RT (>60 1RM) in muscle strength in a wide range of exercises.

PLOS ONE
Very low certainty evidence from three studies [38,41,42] suggested no significant difference between the comparators in bench press 1RM (SMD = -0.17) (Fig 3); however, very low certainty of evidence from one study [37] suggested a significant difference in pectoralis major MVIC in favor of HL-RT (MD = -14.32) ( Table 4). Exclusion of one study including a significantly older population [42] did not change the certainty of evidence, the direction, and the size (SMD = -0.15, 95%CI: -0.90 to 0.59) of the effect estimate (Fig 3). Additionally, very low certainty evidence [42] indicates no significant differences between LL-BFR training and HL-RT training in 1RM shoulder press and seated row exercise (Table 4).
Finally, from a study [42] assessing isometric strength of several upper body muscles in senior individuals (age >59 years), very low certainty evidence indicates no significant differences between LL-BFRT and HL-RT in lower trapezius, external rotation, prone row, seated row, and scapular retraction strength at the 8-week follow-up ( Table 4).

Effects of interventions in muscle size
Muscle size in LL-BFRT compared to LL-RT without BFRT. Three studies [36,39,40] evaluated the effect of LL-BFRT training compared to LL-RT in the size of muscles located proximally to the application of the BFRT by using US, DEXA, or tape measure (S2 Table in S1 File).
Very low certainty evidence suggests a significant increase in shoulder lean mass measured with DEXA in favor of the LL-BFRT group compared to the LL-RT group at the 8-week follow-up (Table 5). Very low certainty evidence of no significant differences between comparators were reported for pectoralis major thickness, and upper and lower chest girth [39,40] ( Table 5). Muscle size in LL-BFRT compared to HL-RT without BFR. Three studies [38,41,42] evaluated the effect of LL-BFRT compared to HL-RT in the size of muscles located proximally to the application of the BFR by using US, DEXA, MRI, or tape measure (S2 Table in S1 File).
Very low certainty evidence [42] suggests a significant increase in pectoralis major thickness (MD = 0.57) in favor of the LL-BFRT group compared to the HL-RT group (Table 5). Very low certainty evidence showed no significant differences between the comparators in deltoid muscle thickness, lean trunk mass, pectoralis muscle CSA, or chest girth ( Table 5).

Effects of interventions in tendon thickness
Tendon thickness in LL-BFRT compared to LL-RT without BFR. Only one study with high risk of bias [35] evaluated the effect of LL-BFRT compared to LL-RT without BFR and reported very low certainty evidence of no significant differences between the comparators in supraspinatus tendon thickness (MD = -0.01 95%CI: -0.05 to 0.02) ( Table 5).

Discussion
The findings of this systematic review suggest that LL-BFRT may result in better strength and size adaptations compared to similar exercise without BFR in muscles proximal to the applied cuff, although the quality of evidence is low, and the findings are mixed. Low and very low certainty evidence suggests a significant increase in bench press 1RM (2-4 weeks) and in shoulder flexion MVIC (6-8 weeks) in favor of the LL-BFRT compared to the LL-RT without BFR group. Conflicting evidence (low and very low certainty) was found for shoulder abduction, scaption, internal and external rotation strength. Very low certainty evidence suggests a significant increase in pectoralis major MVIC in favor of the HL-RT compared to the LL-BFR group at the 4-week follow-up, but evidence (low and very low certainty) of no significant differences in back and shoulder muscles were found between the comparators. Very low certainty evidence suggests no significant differences in measures of chest muscles' size between LL-BFRT and LL-RT without BFR; however, very low certainty evidence indicates a significant effect of LL-BFRT in shoulder lean mass at the 8-week follow-up. In addition, very low certainty evidence indicates conflicting (pectoralis major) or non-significant (deltoid, chest girth, and trunk lean mass) differences between LL-BFRT and HL-RT in muscle size.

Effect of LL-BFRT in muscle strength
Consistent evidence suggests that LL-BFRT induces larger improvements in muscle strength when compared-in both the upper and the lower limb-to LL-RT in young [19,44] and older (>50 years) healthy individuals [30,45,46]. The size of the effect appears to be associated with the age of the healthy participants, the training duration, and the volume of exercise loading [19,[44][45][46][47] however, the measured effect was in muscles distal to the site of applied occlusive pressure of the exercised limb. Contrary to the notion that muscles not exposed to the restrictive stimulus would not have any benefit from the application of BFR, the studies included in the present review provide preliminary evidence for the opposite finding. It has been argued that exercising until volitional exhaustion of the prime mover muscles will increase the required activation of the synergistic muscles involved in the performance of an exercise (e.g., the synergistic involvement of the triceps muscle in the performance of a chest press exercise) and that this increase in activation may elicit increases in strength of muscles located proximal to the BFR cuff [15]. The authors hypothesized that the increasing fatiguing effect on the triceps muscle under BFR would have caused a greater stress and demand on the pectoralis major muscle to compensate for the loss of force production [15]. Studies on the lower limb have shown that LL-BFRT may elicit such adaptations as indicated by an increase in (proximal) hip abductors strength [22] and of the gluteus maximus [43,48]. Several mechanisms of BFR action have been proposed with the metabolic stress upregulating distinct cellular signaling pathways, along with the cell swelling in the hypoxic environment under BFRT being the most popular [4,[49][50][51]. It has been suggested that the intracellular swelling may serve as a stimulus to promote protein synthesis and inhibit proteolysis [22] and it seems that this mechanism is plausible in inducing proximal adaptations as a greater increase in swelling of the chest muscles was observed compared with the triceps at the end of low-load BFR bench press exercises [41].
In the present systematic review, we suggest that the significant between-group differences in muscle strength in favor of the LL-BFRT should be interpreted with caution given the unstandardized protocols with unmatched exercise loading and the diversity of outcome measurement methods. To illustrate, the two studies [34,36] that showed significant improvement in shoulder flexion strength between LL-BFRT and LL-RT: a) varied significantly in the loading parameters used for the LL-BFR group (30% 1RM vs 20% of isometric max), b) used different load progressions over 6 and 8 weeks (load increase by 1 lb per week if 75 repetitions were achieved [36] versus load increase based on a score >7/10 on RPE scale [34], c) had unbalanced training volume (i.e., the fourth set performed to fatigue [36], and d) implemented different exercise programs (one study [34] did not include shoulder flexion exercise at all). Furthermore, significant methodological differences could be noted between the two studies reported favorable outcomes for the LL-BFRT in the bench press 1RM [39,40]. Both studies occluded both upper arms simultaneously (in contrast to the majority of the included studies), while the exercise protocol for the study by Yamanaka et al. [39] involved parallel BFRT of the upper and lower limb showing a significant imbalance in the total time under occlusion, and the muscular tissue under loading and metabolic stress suggesting plausible systemic responses driven by the increased training volume. Similarly, the conflicting evidence in shoulder abduction, internal and external rotation could be attributed as well to the methodological diversity (i.e., no information on the testing position) and the training imbalances (i.e., exercise number imbalance) between studies ( Table 2 & S2 Table in S1 File). For example, the two studies that measured shoulder abduction strength as an outcome incorporated a disproportionate number of exercises: only external rotation [35] compared to five upper limb exercises including resisted shoulder abduction [34].
The evidence regarding LL-BFRT compared to HL-RT in muscle strength of healthy individuals is conflicting, with two systematic reviews showing superiority evidence for HL-RT [6,30] and two others not [30,52]. Our findings for muscles proximal to the BFR application and consequently not directly under BFR, indicate very low certainty evidence that LL-BFRT and HL-RT are equally effective in improving muscle strength. Despite the methodological diversity and inconsistencies, we suggest that LL-BFRT could be used as an alternative intervention for muscle strength improvement even in muscles located proximal to the occlusion site in individuals that cannot train with higher loads.

Effect of LL-BFRT in muscle size
Contemporary evidence suggests that LL-BFRT may elicit significant increases in muscle size when compared to LL-RT without BFR [15] and similar muscle adaptations (size) to HL-RT [6,15,30] in healthy adults and individuals with musculoskeletal conditions [53]. Eight weeks of rotator cuff training with LL-BFRT may induce greater increases than matched LL-RT in the shoulder region muscle mass and in the whole upper limb where muscle mass is assessed using Dual Energy X-Ray Absorptiometry [36]. Notably, no difference between LL-RT with or without BFR was observed in pectoralis major muscle size, thickness, or girth in three studies implementing only chest press exercise [39][40][41]. It seems that the proximal muscle size adaptations may be plausibly driven by the total time under occlusion, a minimum volume threshold, the training period, or a systemic effect (Table 2), rather than the specificity of the exercise performed. The sensitivity of the muscle size measurement method may have played a role in the findings of our review. A significant effect of LL-BFRT was observed only in shoulder lean mass compared to LL-RT measured by DEXA in contrast to studies implementing muscle size/thickness measurements using US or tape measure. The lack of measurable betweengroup differences may stem from the fact that tape [54] and US [55] are not considered as reliable methods for measuring changes in regional muscle size and volume in contrast to DEXA which is considered the gold standard [56]. The measurement method may also explain the contradictory results in pectoralis major size in studies comparing LL-BFRT to HL-RT [41,42]. Nevertheless, in line with previous research [6,15,30], our findings showed that LL-BFRT results in similar muscle size adaptations with HL-RT in muscles not directly under BFR conditions.

Effect of LL-BFRT in tendon thickness
The evidence for the effect of BFRT on tendon structural and physiological adaptations is sparse in both healthy [47, 57,58] and individuals with musculoskeletal conditions [59,60]. In the Achilles and patellar tendons of healthy individuals, findings suggest within-group increases in tendon thickness (at 12-weeks) which were at least comparable to HL-RT without BFR [47, 57] and were consistent with our findings for the supraspinatus tendon (at 8-weeks)despite being proximal to the BFR application. The load magnitude did not seem to play a major role in these adaptions, as the lower limb tendon studies compared LL-BFRT to HL-RT, while in the supraspinatus tendon study [35] the BFRT was compared to LL-RT. Nevertheless, given the limited number of available studies along with the evident variability in normal tendon thickness, the suggestions of loading for at least 14 weeks for optimal tendon adaptations, and the limitations of the thickness measurement methods [61][62][63], these results should be interpreted with caution.

Limitations
The lack of standardized protocols, methodology, and measurement methods did not permit extended quantitative synthesis and limits the generalizability of our findings. Along with the small number of relevant studies, several other individual-study factors contributed to this limitation, including the total number of exercises performed, the application of BFR only in the upper or in both upper and lower limbs, the total time under loading and occlusion, singlelimb of bilateral training, and bilateral of contralateral limb training. We also acknowledge that the limited number of the included studies did not allow performance of some of the standard analyses of a systematic review as for example the assessment of publication bias using funnel plots or related regression methods. A standardized method of BFR study reporting and protocol of application should be established in future research allowing for optimization in the evidence translation into clinical practice.

Practical applications
Contrary to common resistance training guidelines and BFR mechanisms of action hypotheses, increases in strength and size of muscle proximal to BFR application can be achieved using low loads. Evidence suggests that performing light LL-BFR causes systemic hypoalgesia comparable with HL-RT in healthy individuals [64] and patients with anterior knee pain [65,66] and produces cross-over contralateral limb (upper and lower) loading adaptations [22,34]. Plausibly, these results and the reported contralateral and whole-body cross-over effects [43] may be explained by a systemic response to LL-BFRT. Nevertheless, current assumptions are mainly based on indirect observations [43] and further research is required to evaluate these effects.
In the upper limb in muscles distal to the BFR application, the effect of LL-BFRT appears similar to HL-RT and seems to be minimally affected by variability in the intensity and the occlusive pressure implemented (Table 2). Clinicians may see this as a window of opportunity for loading exercises in populations that are not cleared or capable of using higher loads (i.e., musculoskeletal pathology). There was considerable heterogeneity in the prescribed exercise parameters which were observed to induce positive adaptations. We suggest that an important area of future research is determining the minimal exercise intensity and loading volume for beneficial proximal adaptations to occur.

Conclusion
Low and very low certainty evidence suggests a significant increase in bench press 1RM and in shoulder flexion MVIC in favor of the LL-BFRT compared to the LL-RT without BFR, and very low certainty evidence of a significant increase in shoulder lean mass at the 8-week follow-up, but these findings should be interpreted with caution. LL-BFRT elicits comparable muscle adaptations (strength and size) in shoulder girdle muscles to both LL-and HL-RT. The minimal volume threshold and the total time under occlusion required for beneficial responses are yet to be described.
Supporting information S1 File. Table 1 is the search strategy and results in databases, Table 2